IDH2 (isocitrate dehydrogenase 2 (NADP+), mitochondrial)

2017-07-01   Jean Loup Huret , Philippe Dessen 

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH); UMR1170 INSERM, Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France PHD)




Human Isocitrate dehydrogenase (IDH) occurs in three isozymes, IDH1, located in the cytoplasm, and IDH2 and IDH3 located in the mitochondria. IDH functions as part of the tricarboxylic acid (TCA) cycle and catalyzes the reversible conversion of isocitrate to alpha ketoglutarate (α-KG)\/2-oxoglutarate (2-OG), thus promoting the activity of dioxygenases that require α-KG as a cosubstrate. IDH1 and IDH2 use NADP+ as a cofactor, producing NADPH in the process (NADPH plays a vital role in the regeneration of the antioxidant glutathione), whereas IDH3 uses NAD+ as a cofactor and produces NADH. Somatic heterozygous mutations in the active site of IDH1 (at position R132) or IDH2 (at position R140 or R172) have been reported in a spectrum of human tumors : gliomas, hematologic malignancies including myeloproliferative neoplasms, myelodysplastic syndromes and acute myeloid leukemia, and also angioimmunoblastic T-cell lymphoma and primary central nervous system lymphoma, cholangiocarcinoma, chondrosarcomas, and other malignancies. IDH mutations lead to a neomorphic enzymatic activity of the mutated IDH enzyme, resulting in the conversion of α-KG to R-2-hydroxyglutarate (R2-HG). Supra-normal levels of intracellular 2-HG interfere with several α-KG-dependent dioxygenases, notably enzymes involved in methylation of histones (histone lysine demethylases, KDMs) and DNA (TET family of DNA hydroxylases).



Alternative splicing of IDH2 gene results in multiple transcript variants. [provided by RefSeq, Feb 2014]
Atlas Image
Genomic location of the three IDH2 isoforms on chr15q26.3 (build hg19) transcribed in the reverse strand of the genome (UCSC or RefSeq).


The various isocitrate dehydrogenases are :
IDH1 isocitrate dehydrogenase 1 (NADP+), an homodimer located in 2q33.3, localized in cytoplasm ,
IDH2 isocitrate dehydrogenase 2 (NADP+), mitochondrial, located in 15q26.1, localized in mitochondria
IDH3 isocitrate dehydrogenase 3 (NAD+) , composed of 3 subunits (IDH3A, 15q25.1) , (IDH3B, 20p13), and IDH3G, Xq28), localized in mitochondrion .


The sequence of IDH2 is defined by 610 GenBank accessions from 560 cDNA clones, some from brain (seen 50 times), liver (31), prostate (22), testis (20), uterus (19), colon (18), stomach (17) and 141 other tissues (from Acembly).
IDH2 gene has 3 transcript isoforms (RefSeq):
IDH2 at chr15:90627211-90645786 - (NM_002168) isocitrate dehydrogenase [NADP], mitochondrial isoform 1 precursor (Genomic size: 18576; strand -, 11 exons).IDH2 at chr15:90627211-90643853
- (NM_001289910) isocitrate dehydrogenase [NADP], mitochondrial isoform 2 (Genomic size: 16643; strand -, 11 exons).
IDH2 at chr15:90627211-90645786 - (NM_001290114) isocitrate dehydrogenase [NADP], mitochondrial isoform 3 (Genomic size: 18576; strand -, 9 exons).
On the other hand enSembl cites 5 transcripts and 4 phenotypes.


In the human genome exists an IDH1 pseudogene in 6p24, (B4DXS4_HUMAN, chr6: 7516836-7517533 ) homolog of IDH2 (92%) present in monkeys (99.1% identity with the NM_001265779.2 transcript in the case of Rhesus). 


Atlas Image
Structure of the primary sequence of IDH2 with the main features.


The 3 IDH2 isoforms have 452, 400 and 332 amino acids (aa) respectively and are homodimers. The differences are in the NH2 part. UNIPROT cites uniquely 2 isoforms (P48735-1, 452 aa, and P48735-2, 400 aa) [ ]. The third isoform deduced from RefSeq lacks 120 NH2 aa.
3D_Structure The first 3D structure solved in human was the homodimer IDH1 (wild type and mutant R132 (UNIPROT:P75874 and PDB: 3mar, Yang et al, 2010). The first structure of mammalia IDH2 was that of Sus Scrofa (UNIPROT: P33198 and PDB: 1wld, Ceccarelli et al, 2002). The 3D structure of human IDH2 (mutated as R140Q) has been realized as a complex with an IDH2 inhibitor (PDB: 4ja8, Wang et al., 2013) by replacement in IDH1 structure. All these structures belong to the superfamily c.77.1: Isocitrate/Isopropylmalate dehydrogenase-like, a class of alpha and beta proteins (a/b) and a fold consisted of two intertwined (sub)domains related by pseudo dyad; the constituent families contains a typical Rossman fold of dehydrogenase to adapt the binding of NAD(P)+ and form similar dimers with the active site between the two identical subunits (
Atlas Image
Comparison of primary structures of mitochondrial (IDH2; P48735) and cytoplasmic (IDH1 ; P75874) isocitrate dhydrogenases (73% identity). * denote the two arginines R140 and R172.


The IDH2 gene is expressed at very high level, 5 times the average gene expression. IDH2 is expressed particularly at higher level in heart, stomach, muscle, thymus, kidney.
Atlas Image
3D structure of the human IDH2 dimer (modelised by SwissModel from Sus Scrofa IDH2 complexed with Mn2+ isocitrate (PDB:1wld) (panel A). Topological secondary structure of IDH2 mutated (PDB:4ja8) (from PDBSum : (panel B) with the position of the two potential mutations (R140 and R172).


Mitochondrion; Translated in the cytoplasm, IDH2 goes to mitochondrial matrix via a specific transit peptide NH2 (1-45).
Atlas Image
IDH occurs in three isoforms, IDH1, located in the cytoplasm, IDH2 and IDH3, located in the mitochondria, which function as part of the tricarboxylic acid (TCA) cycle or "Krebs cycle" IDH proteins catalyze the oxidative decarboxylation of isocitrate to produce CO2 and alpha-ketogluatarate (α-KG). The reaction requires the presence of the cofactor NADP+ as electron acceptor, generating nicotinamide adenine dinucleotide phosphate (NADPH). IDH1 and IDH2, are homodimeric enzymes.


This protein catalyzes the oxidative decarboxylation of isocitrate to 2-oxoglutarate and is specific of NADP(+). IDH2 plays a role in intermediary metabolism and energy production. It may tightly associate or interact with the pyruvate dehydrogenase complex.

Catalytic activity EC: . For the wild type enzyme the catalytic reaction is :
Isocitrate + NADP(+) -> 2-oxoglutarate + CO(2) + NADPH.
In mutated forms (R140 or R172), there is an abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate (2-HG).
Isocitrate + NADP(+) -> 2-hydrocyglutarate + CO(2) + NADPH.

Cofactor Mg(2+); Mn(2+). 1 Mg(2+) or Mn(2+) ion per subunit. Required for activity.
This second specific activity is related to the role of 2-HG as inhibitor of enzymes implicated in demethylation of DNA (TET2 and other demethylases) (Nakajima et al. 2014, Scourzic et al, 2015).

Post translational modification Acetylation at Lys-413 dramatically reduces catalytic activity.

Atlas Image
Role of IDH2 in TCA cycle and of the mutated form in inhibition of demethylation pathways .by competition of 2-HG for the α-KG on TET2 (adapted from Nakajima , 2014).


In molecular biology, the isocitrate/isopropylmalate dehydrogenase family is a protein family consisting of the evolutionary related enzymes isocitrate dehydrogenase, 3-isopropylmalate dehydrogenase and tartrate dehydrogenase. IDH is well conserved in eucaryota in a two separate lineages (cytoplasmic, IDHC or IDH1 and mitochondrial, IDHP or IDH2)(AI et al, 2014). The mammalian NADP+-IDH2 enzyme are structurally compared with the previously solved structures of IDH from E. coli and Bacillus subtilis that share 16 and 17% identity, respectively, with the mammalian enzyme. The mammalian enzyme has a protein fold similar to the bacterial IDH structures with each monomer folding into two domains. However, considerable differences exist between the bacterial and mammalian forms of IDH in regions connecting core secondary structure. In human IDH1 and IDH2 have 72 % identity.



The COSMIC database (v75) displays 88 unique mutations for 38867 samples
The main mutations of IDH2 are R140Q and R172K in haematopoeitic and central nervous system neoplasms
Atlas Image
Repartition of IDH2 mutations (in great part on aa R140 and R172) in different sites and tumors (limited to more or equal than 3)
Atlas Image
Mutated IDH1/2 result in the conversion of alpha ketoglutarate (α-KG) to hydroxyglutarate (2-HG). 2-HG acts as an antagonist of α-KG.
Atlas Image
α-KG is a substrate for methyl-cytosine demethylation by TET family proteins (DNA demethylation at CpG islands)
α-KG is a substrate for histone demethylation by Jumonji (JMJ) histone demethylases.

Implicated in

Top note
Somatic point mutations in IDH1/2 confer a gain-of-function in cancer cells. Mutated IDH1/2 results in the conversion of alpha ketoglutarate to hydroxyglutarate (2-HG) an oncometabolite, leading to hypermethylation and a block in cell differentiation
α-KG dependent dioxygenases hydroxylate various substrates and regulate many cellular pathways (collagen, histones, transcription factors, alkylated DNA and RNA, lipids).
2-HG is structurally similar to and acts as an antagonist of α-KG.
High levels of 2-HG lead to hypermethylation, resulting in epigenetic alterations of DNA and histone proteins and in a block in cell differentiation
2-HG competitively inhibits α-KG dependent dioxygenases, including histone/DNA demethylases
  • Jumonji (JMJ) family histone demethylases which control nearly all histone demethylation (for example KDM2A, KDM4A, KDM6A, KDM3B and KDM4C) and
  • methylcytosine dioxygenases of the TET (ten-eleven translocation) family, which play a a key role in the process of DNA demethylation at CpG islands and other sites (Yen et al., 2010; Cairns et al., 2012; Yang et al., 2012; Lemonnier et al., 2016; Mondesir et al., 2016; Stein et al., 2016; Ku and Park, 2017).
    IDH2 mutation induces DNA hypermethylation and inhibits mesenchymal lineage differentiation in correlation with high levels of 2-HG accumulation. IDH2 mutant cells escape contact inhibition (Lu et al. 2013).
    SIRT5 regulates cellular NADPH homeostasis and redox potential by promoting IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense (Zhou et al., 2016). IDH2 downregulation increases NF-?B activation and CHUK (IkBα) phosphorylation and elevates MMP9 activation (Yi et al., 2016).
  • Entity name
    Various malignancies
    Mutations in IDH1 (in particular c.394C>T encoding a R132C substitution (affecting Arg132) and c.395G>A encoding a R132H substitution) or IDH2 (in particular c.516G>C encoding R172S) occur in 80% of WHO grade II-IV glioma, 60% of chondrosarcoma, 40% of angioimmunoblastic T-cell lymphoma, 20% of acute myeloid leukaemia (AML), 20% of intrahepatic cholangiocarcinoma, 12% of skin melanoma, 10% of acute lymphocytic leukaemia, and 5% of colorectal cancer, see below (Molenaar et al 2017).
    IDH1 mutations are much more frequent than IDH2 mutations in glioma (95%), chondrosarcoma (95%) and cholangiocarcinoma (80%), whereas IDH2 mutations are equally or more frequent in blood malignancies: chronic myeloproliferative diseases (MPD) 2%, myelodysplasia (MDS) 2-7%, acute myeloid leukemia (AML) 8-19%, angioimmunoblastic T-cell lymphoma 20-42%, versus IDH1 mutations: MPD <1%, MDS 2-3%, AML 6-16% (Mondesir et al., 2016). In addition, only IDH2 mutations have been reported in angioimmunoblastic T-cell lymphoma, osteosarcoma and gastric cancer (Molenaar et al., 2015).
    International cancer programs studies demonstrated frequent IDH2 mutations in acute myeloid leukemia, glioma, cholangiocarcinoma and primary central nervous system lymphoma (WHO 9680/3), but also to a lesser extend uterine carcinosarcoma, skin melanoma, and rare mutations in, colorectal carcinoma, bladder urothelial carcinoma, head and neck squamous cell carcinoma, cutaneous squamous cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma and renal papillary carcinoma (see Figure below) (cbioportal)
    IDH2 was also reported to be downregulated in melanoma (Park et al., 2008), colon carcinoma (Lu et al., 2012) and osteosarcoma (Yi et al., 2016).
    IDH2 amplification was found mainly in breast cancer, esophageal carcinoma, stomach adenocarcinoma, pancreatic adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus carcinoma, neuroendocrine prostate cancer and various other cancers (see second Figure below) (cbioportal).
    Atlas Image
    Alterations in IDH2 in various cancers (from international cancer programs studies): Green: mutations; Red: amplification; Blue: deletion. Abbreviations: AML: acute myeloid leukemia; PCNSL: primary central nervous system lymphoma; UCS: uterine carcinosarcoma; CSCC: cutaneous squamous cell carcinoma; MDS: myelodysplasia; NEPC: neuroendocrine prostate cancer. Screenshot from
    Atlas Image
    Mutations in IDH2 in various cancers (from international cancer programs studies): Mutations (red pots) were found in the following: Acute myeloid leukemia, Cholangiocarcinoma, Colorectal carcinoma, Glioma, Head and Neck squamous cell carcinoma, Hepatocellular carcinoma, Lung adeno carcinoma, Skin melanoma, Pancreatic adeno carcinoma, Uterine Carcinosarcoma, Renal Clear cell carcinoma and Renal papillary carcinoma. Screenshot from
    Entity name
    Glioma: Diffuse astrocytic and oligodendrogial tumors and Neuronal and mixed neuronal-glial tumors
    The 2016 World Health Organization (WHO) classification of tumors of the central nervous system takes into account IDH1 or IDH2 exon 4 mutations (in IDH1 codon 132 and IDH2 codon 172) as a crucial step in the characterization of gliomas.
    Mutations in IDH1 or IDH2 occur in the vast majority of low-grade gliomas and secondary high-grade gliomas, and they occur early in gliomagenesis. The mutations drive increased methylation in gliomas (Cohen et al., 2013). IDH1 is mutated in 40% of gliomas (roughly 70% of low-grade gliomas, 50% of grade III, and 5 to 10% of primary glioblastomas) in some studies, to 75% in other studies, and IDH2 is mutated in about 2% of gliomas. Most common mutations were: R132H, R132C, R132G, R132S, R132L in IDH1 and R172K, R172M, and R172W in IH2. IDH1/IDH2 mutations are associated with genomic profile, being present in nearly all the 1p19q codeleted gliomas, and virtually absent in gliomas with EGFR amplification. It is a strong and independent predictor of survival (Rossetto et al., 2011; Yang et al., 2012).
    The WHO grade II diffuse astrocytomas and WHO grade III anaplastic astrocytomas are divided into IDH-mutant and IDH-wildtype tumors. The IDH-mutant category is much more frequent. The prognostic differences between IDH-mutant WHO grade II diffuse astrocytomas and WHO grade III anaplastic astrocytomas may not be very different. The prognosis of patients with IDH1/2 mutations has been shown to be significantly better than the prognosis of patients with wild-type IDH1/2 in both grades II diffuse astrocytomas and grade III anaplastic astrocytoma.
    Glioblastomas are divided in the 2016 entral nervous system WHO/OMS classification into IDH-wildtype glioblastoma (90 % of cases), most frequently primary or de novo glioblastoma in patients over 55 years, and IDH-mutant glioblastoma (10 %), most often secondary glioblastoma with a history of prior lower grade diffuse glioma in younger patients. The prognosis of the IDH-mutant cases appears more favorable.
    The diagnosis of oligodendroglioma and anaplastic oligodendroglioma requires the demonstration of both an IDH gene family mutation and combined 1p/19q loss.
    IDH mutations are absent in tumors of childhood that histologically resemble oligodendroglioma, and also in neuronal and mixed neuronal-glial tumors (Louis et al., 2016).
    IDH1 and IDH2 are mutually exclusive in gliomas, and IDH2 mutations are mutually exclusive with PTEN , TP53 and ATRX mutations. Patients with IDH2 mutations had a higher frequency of 1p/19q co-deletion than IDH1 mutant patients (Wang et al., 2016).
    Entity name
    Chronic myeloproliferative syndromes
    IDH2 R140Q and IDH2 R172K mutations can occur in 2% of primary myelofibrosis. IDH2 mutations can also occur in polycythemia vera (1.5%) or essential thrombocythemia (<1%) (Tefferi et al., 2010). IDH1/2 mutations confer worse prognosis in patients with myelofibrosis. Primary myelofibrosis with SRSF2 mutations have frequent IDH1 and IDH2 mutations (Lasho et al., 2012).
    Entity name
    Myelodysplastic syndromes (MDS)
    IDH2 R140Q and IDH2 R172K mutations have been found in about 6% of cases of refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, chronic myelomonocytic leukemia and secondary acute myeloid leukemia. IDH gene mutations did not have any impact on overall survival (Kosmider et al.,2010).
    Entity name
    Acute myeloid leukemia (AML)
    DNMT3A , IDH1, IDH2 and TET proteins play a key role in the process of DNA methylation/demethylation and mutant proteins impairs myeloid differentiation. IDH1/2 and TET2 mutations in acute myeloid leukemia are mutually exclusive in most cases (Paschka et al., 2010; Solary et al., 2014).
    IDH2 mutations are more frequent than IDH1 mutations in AML. IDH2 mutations occur in 9 to 16% of AML cases, according to various large studies. IDH2 mutations are mainly R140Q mutations and R172K mutations. IDH1/2 mutations were associated with older age, lower WBC, higher platelets, normal karyotype, and NPM1 mutations.
    IDH1 mutated cases of myeloid leukemia (MDS and AML) also harbored more DNMT3A, PHF6 and FLT3 mutations, whereas whereas IDH2 mutated cases were enriched in ASXL1, SRSF2 , RUNX1, STAG2 mutations.
    Data on prognostic significance of IDH1/2 mutations in AML has been conflicting. IDH1 or IDH2 mutations may confer sensitivity to novel therapeutic approaches, including the use of demethylating agents (Mardis et al., 2009; Abbas et al., 2010; Paschka et al., 2010; Haferlach et al., 2013; Im et al., 2014; Molenaar et al., 2015).
    Angioimmunoblastic T-cell lymphoma (AITL) (WHO 9705/3) is one of the most frequent nodal peripheral T-cell lymphomas.
    Mutations are almost exclusively restricted to IDH2 R172 (Lemonnier et al., 2016).
    IDH2 was mutated (R172K, R172G, R172T, and R140G mutations) in about 20% of angioimmunoblastic T-cell lymphomas, but not in other peripheral B or T-cell leukemia/lymphoma (Hodgkin lymphoma, non-Hodgkin B-cell lymphoma, B-cell acute lymphoblastic lymphoma, T-cell acute lymphoblastic lymphoma, anaplastic large cell lymphoma, enteropathy type T-cell lymphoma, cutaneous T-cell lymphoma, hepatosplenic T-cell lymphoma, extranodal NK/T-cell lymphoma). This is the second most frequent mutation to be identified after TET2 in angioimmunoblastic T-cell lymphoma. It does not show prognostic significance. Overall survival and progression-free survival were identical in patients with wild-type or mutant IDH2 (Cairns et al., 2012).
    Primary central nervous system lymphoma (WHO 9680/3) is a mature B-cell neoplasm. IDH2 mutations were identified in approximately 10% of PCNSL ( see above figures from cbioportal).
    Entity name
    Familial hematological malignancies
    Germline IDH mutations were searched for in 104 familial cases of hematological malignancies/cosegregated solid tumors. IDH1 and IDH2 variants were found respectively in 15 % and 3% of cases (Hamadou et al., 2016).
    Entity name
    Cholangiocarcinoma is an aggressive malignancy with poor prognosis. Mutations in IDH1 and IDH2 were found only in 23% of cholangiocarcinomas of intrahepatic origin, in none of the extrahepatic cholangiocarcinomas and rarely (2%) in the other common gastrointestinal malignancies (colorectal, gastroesophageal, liver, pancreatic, and small intestine carcinomas). IDH1 mutations are the most frequent (11%-24%) and IDH2 mutations are seen in 2%-6% of the cases. The IDH1 mutation was R132C, R132L, or R132G, and the IDH2 mutation was R172W, and neither the common glioma mutation R132H of IDH1 nor the common AML mutation at codon R140 of IDH2 was found in cholangiocarcinomas. KRAS, TP53, NRAS, BRAF, AKT1 and PTEN mutations were found each in 3-5% of intrahepatic cholangiocarcinomas (Borger et al., 2012; Borger et al., 2014).
    Entity name
    17-24% of primary malignant bone tumors are chondrosarcoma; enchondroma is a benign precursor of chondrosarcoma. While most enchondromas are solitary, patients with Olliers disease and Maffuccis syndrome (see below) demonstrate multiple enchondromas (Bovée 2002).
    A large retrospective study of Ollier and Maffucci patients was conducted. Overall incidence of development of chondrosarcoma was 40%. Patients with enchondromas located in long bones or axial skeleton, especially the pelvis, have an increased risk of developing chondrosarcoma (Verdegaal et al., 2011).
    More than 50% of patients with chondrosarcomas exhibit gain-of-function mutations in IDH1 or IDH2. IDH mutations were associated with DNA hypermethylation at CpG islands enriched for genes implicated in stem cell maintenance/differentiation and lineage specification. Introduction of mutant IDH2 in murine mesenchymal progenitor cells generated undifferentiated sarcomas (Lu et al., 2013).
    Entity name
    Enchondromas, Ollier disease and Maffucci syndrome
    Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple central cartilaginous tumors (enchondromas) in Ollier disease, accompanied with soft tissue hemangiomas (spindle cell type) or, less commonly, lymphangiomas in Maffucci syndrome.
    Somatic heterozygous mutations in IDH1 (R132C or R132H substitution) or IDH2 (R172S substitution) were found in 87% of enchondromas and in 70% of spindle cell hemangiomas. About 80% subjects with Ollier disease or Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors (while mutations of PTH1R are found in a 10% of patients with Ollier disease). Mesenchymal tumors, including cartilaginous tumors, osteosarcomas and other bone and soft tissue tumors, were screened for IDH1/IDH2 mutations. Heterozygous somatic IDH1/IDH2 mutations were only detected in central and periosteal cartilaginous tumors, and were found in at least 56% of these. The ratio of IDH1/IDH2 mutation was 10.6/1. No germline mutations were detected. No mutations were detected in peripheral chondrosarcomas and osteochondromas. Low level of mutated DNA was identified in non-neoplastic tissue, a finding compatible with a model in which IDH1 or IDH2 mutations represent early post-zygotic occurrences in Ollier disease and Maffucci syndromes (Amary et al., 2011a; Amary et al., 2011b; Pansuriya et al., 2011).
    IDH2 and TP53 mutations have been found correlated with gliomagenesis in a patient with Maffucci syndrome (Moriya et al., 2014).
    Entity name
    Lung cancer
    A higher risk was observed in lung cancer patient carriers of rs11540478 TT and CT compared with CC carriers (Li et al., 2017).
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    Breast cancer
    Solid papillary carcinoma with reverse polarity is a rare breast cancer subtype. Ten of 13 (77%) solid papillary carcinoma with reverse polarity harbored hotspot mutations at R172 IDH2, of which 8 of 10 also displayed mutations in PIK3CA or PIK3R1 (Chiang et al., 2016).
    Entity name
    D-2-Hydroxyglutaric aciduria
    IDH2 mutations were found in a subset of n patients with D-2-hydroxyglutaric aciduria, a neurometabolic inherited disorder. Patients exhibit cardiomyopathy, epilepsy, developmental delay and limited life span (Kranendijk Met al., Science. 2012).
    Entity name
    Parkinsons disease
    Reduced IDH2 facilitates apoptotic cell death induction due to elevated mitochondrial oxidative stress and contributes to degeneration of the dopaminergic neuron in the neurotoxin model of Parkinsons disease (Kim et al., 2016).
    Entity name
    Cardiovascular disease
    IDH2 functions as an antioxidant and anti-apoptotic protein by supplying NADPH to antioxidant systems. Attenuated IDH2 expression resulted in reactive oxygen species-mediated cell death, which contributes to the pathophysiology of cardiovascular disease and myocardial dysfunction (Ku and Park. 2017), and mutant IDH2 causes cardiomyopathy and neurodegeneration in mice (Akbay, 2014).


    Pubmed IDLast YearTitleAuthors
    205388002010Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value.Abbas S et al
    243743362014Parallel evolution of IDH2 gene in cetaceans, primates and bats.Ai WM et al
    245897772014D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice.Akbay EA et al
    215982552011IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours.Amary MF et al
    220572362011Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2.Amary MF et al
    244783802014Circulating oncometabolite 2-hydroxyglutarate is a potential surrogate biomarker in patients with isocitrate dehydrogenase-mutant intrahepatic cholangiocarcinoma.Borger DR et al
    221803062012Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping.Borger DR et al
    220809452012Altered cancer cell metabolism in gliomas with mutant IDH1 or IDH2.Borodovsky A et al
    241069512013Genomic landscapes and clonality of de novo AML.Brewin J et al
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    222158882012IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma.Cairns RA et al
    237964612013Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities.Cairns RA et al
    236349962013Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.Ley TJ et al
    122070252002Crystal structure of porcine mitochondrial NADP+-dependent isocitrate dehydrogenase complexed with Mn2+ and isocitrate. Insights into the enzyme mechanism.Ceccarelli C et al
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    279134352016IDH2 Mutations Define a Unique Subtype of Breast Cancer with Altered Nuclear Polarity.Chiang S et al
    235323692013IDH1 and IDH2 mutations in gliomas.Cohen AL et al
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    256788372015New developments in the pathogenesis and therapeutic targeting of the IDH1 mutation in glioma.Dimitrov L et al
    275919902016Familial hematological malignancies: new IDH2 mutation.Hamadou WS et al
    88331601996Assignment of the human mitochondrial NAD+ -specific isocitrate dehydrogenase alpha subunit (IDH3A) gene to 15q25.1-->q25.2by in situ hybridization.Huh TL et al
    26826541989Structure of a bacterial enzyme regulated by phosphorylation, isocitrate dehydrogenase.Hurley JH et al
    246993052014DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies.Im AP et al
    17489991991Three-dimensional structure of a highly thermostable enzyme, 3-isopropylmalate dehydrogenase of Thermus thermophilus at 2.2 A resolution.Imada K et al
    257069862015Metabolic reprogramming in mutant IDH1 glioma cells.Izquierdo-Garcia JL et al
    253989402015IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition.Kernytsky A et al
    271422422016IDH2 deficiency promotes mitochondrial dysfunction and dopaminergic neurotoxicity: implications for Parkinson's disease.Kim H et al
    254953922015IDH2 mutation in gliomas including novel mutation.Koh J et al
    223438962012Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation.Koivunen P et al
    203760842010Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms.Kosmider O et al
    223919982012Progress in understanding 2-hydroxyglutaric acidurias.Kranendijk M et al
    268653872017Downregulation of IDH2 exacerbates H2O2-mediated cell death and hypertrophy.Ku HJ et al
    229684642012SRSF2 mutations in primary myelofibrosis: significant clustering with IDH mutations and independent association with inferior overall and leukemia-free survival.Lasho TL et al
    249952862014Potential mitochondrial isocitrate dehydrogenase R140Q mutant inhibitor from traditional Chinese medicine against cancers.Lee WY et al
    279566312016The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development.Lemonnier F et al
    247168382014High expression of 5-hydroxymethylcytosine and isocitrate dehydrogenase 2 is associated with favorable prognosis after curative resection of hepatocellular carcinoma.Liu WR et al
    244032542013Isocitrate dehydrogenase 2 mutation is a frequent event in osteosarcoma detected by a multi-specific monoclonal antibody MsMab-1.Liu X et al
    241723282013Anticancer drugs: IDH2 drives cancer in vivo.Lokody I et al
    271579312016The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary.Louis DN et al
    240657662013Induction of sarcomas by mutant IDH2.Lu C et al
    223439012012IDH mutation impairs histone demethylation and results in a block to cell differentiation.Lu C et al
    87078891996Expression of human mitochondrial NADP-dependent isocitrate dehydrogenase during lymphocyte activation.Luo H et al
    232267292012Altered expression levels of IDH2 are involved in the development of colon cancer.Lv Q et al
    196571102009Recurring mutations found by sequencing an acute myeloid leukemia genome.Mardis ER et al
    241069502013Genomic landscapes and clonality of de novo AML.Miller CA et al
    286018262017Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with IDH1-mutated or IDH2-mutated solid tumours.Molenaar RJ et al
    276216792016IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives.Mondesir J et al
    243447542014IDH2 and TP53 mutations are correlated with gliomagenesis in a patient with Maffucci syndrome.Moriya K et al
    244189922014Isocitrate dehydrogenase (IDH)2 R140Q mutation induces myeloid and lymphoid neoplasms in mice.Mylonas E et al
    250407942014TET2 as an epigenetic master regulator for normal and malignant hematopoiesis.Nakajima H et al
    240490962013Novel cases of D-2-hydroxyglutaric aciduria with IDH1 or IDH2 mosaic mutations identified by amplicon deep sequencing.Nota B et al
    89547901996Assignment of the human mitochondrial NADP(+)-specific isocitrate dehydrogenase (IDH2) gene to 15q26.1 by in situ hybridization.Oh IU et al
    257011982015IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II-III diffuse gliomas.Olar A et al
    220572342011Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome.Pansuriya TC et al
    184844102008Inactivation of mitochondrial NADP+-dependent isocitrate dehydrogenase by hypochlorous acid.Park SY et al
    205670202010IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication.Paschka P et al
    224172032012Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.Patel JP et al
    218850762011Metabolism of glioma and IDH1/IDH2 mutations.Rossetto M et al
    250430452014Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer.Saha SK et al
    256323052015TET proteins and the control of cytosine demethylation in cancer.Scourzic L et al
    281937792017Combination Targeted Therapy to Disrupt Aberrant Oncogenic Signaling and Reverse Epigenetic Dysfunction in IDH2- and TET2-Mutant Acute Myeloid Leukemia.Shih AH et al
    5640831977Somatic cell genetic assignment of the human gene for mitochondrial NADP-linked isocitrate dehydrogenase to the long arm of chromosome 15.Shimizu N et al
    242202732014The Ten-Eleven Translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseases.Solary E et al
    265537502016Molecular Pathways: IDH2 Mutations-Co-opting Cellular Metabolism for Malignant Transformation.Stein EM et al
    205086162010IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis.Tefferi A et al
    284614092017Optimizing Next-Generation AML Therapy: Activity of Mutant IDH2 Inhibitor AG-221 in Preclinical Models.Thomas D et al
    80536751994Tartrate dehydrogenase, a new member of the family of metal-dependent decarboxylating R-hydroxyacid dehydrogenases.Tipton PA et al
    221470002011Incidence, predictive factors, and prognosis of chondrosarcoma in patients with Ollier disease and Maffucci syndrome: an international multicenter study of 161 patients.Verdegaal SH et al
    261880142016Isocitrate dehydrogenase mutations in gliomas.Waitkus MS et al
    235581732013Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation.Wang F et al
    272456972016The comparison of clinical and biological characteristics between IDH1 and IDH2 mutations in gliomas.Wang HY et al
    201711472010The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate.Ward PS et al
    253249722014Mutations in the isocitrate dehydrogenase 2 gene and IDH1 SNP 105C > T have a prognostic value in acute myeloid leukemia.Willander K et al
    192286192009IDH1 and IDH2 mutations in gliomas.Yan H et al
    209757402010Molecular mechanisms of "off-on switch" of activities of human IDH1 by tumor-associated mutation R132H.Yang B et al
    230713582012IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives.Yang H et al
    260490212015IDH1, a CHOP and C/EBPβ-responsive gene under ER stress, sensitizes human melanoma cells to hypoxia-induced apoptosis.Yang X et al
    281937782017AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations.Yen K et al
    267826302016Downregulation of IDH2 exacerbates the malignant progression of osteosarcoma cells via increased NF-κB and MMP-9 activation.Yi WR et al
    224161402012SIRT3 protein deacetylates isocitrate dehydrogenase 2 (IDH2) and regulates mitochondrial redox status.Yu W et al
    77731801995Modeling substrate binding in Thermus thermophilus isopropylmalate dehydrogenase.Zhang T et al
    271137622016SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense.Zhou L et al

    Other Information

    Locus ID:

    NCBI: 3418
    MIM: 147650
    HGNC: 5383
    Ensembl: ENSG00000182054


    dbSNP: 3418
    ClinVar: 3418
    TCGA: ENSG00000182054


    Gene IDTranscript IDUniprot

    Expression (GTEx)



    PathwaySourceExternal ID
    Citrate cycle (TCA cycle)KEGGko00020
    Glutathione metabolismKEGGko00480
    Citrate cycle (TCA cycle)KEGGhsa00020
    Glutathione metabolismKEGGhsa00480
    Metabolic pathwaysKEGGhsa01100
    Citrate cycle, first carbon oxidation, oxaloacetate => 2-oxoglutarateKEGGhsa_M00010
    Citrate cycle (TCA cycle, Krebs cycle)KEGGM00009
    Citrate cycle, first carbon oxidation, oxaloacetate => 2-oxoglutarateKEGGM00010
    2-Oxocarboxylic acid metabolismKEGGhsa01210
    2-Oxocarboxylic acid metabolismKEGGko01210
    Biosynthesis of amino acidsKEGGhsa01230
    Biosynthesis of amino acidsKEGGko01230
    Carbon metabolismKEGGhsa01200
    Carbon metabolismKEGGko01200
    Citrate cycle (TCA cycle, Krebs cycle)KEGGhsa_M00009
    The citric acid (TCA) cycle and respiratory electron transportREACTOMER-HSA-1428517
    Pyruvate metabolism and Citric Acid (TCA) cycleREACTOMER-HSA-71406
    Citric acid cycle (TCA cycle)REACTOMER-HSA-71403

    Protein levels (Protein atlas)

    Not detected


    Entity IDNameTypeEvidenceAssociationPKPDPMIDs


    Pubmed IDYearTitleCitations
    192286192009IDH1 and IDH2 mutations in gliomas.1558
    211307012010Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation.875
    223439012012IDH mutation impairs histone demethylation and results in a block to cell differentiation.626
    201711472010The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate.617
    260617532015Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors.412
    221063022011Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability.365
    195543372009Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas.316
    195543372009Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas.316
    215982552011IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours.243
    201424332010Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations.240


    Jean Loup Huret ; Philippe Dessen

    IDH2 (isocitrate dehydrogenase 2 (NADP+), mitochondrial)

    Atlas Genet Cytogenet Oncol Haematol. 2017-07-01

    Online version: